Necrotizing enterocolitis (NEC) is a disease affecting premature infants with potentially devastating complications in the neonatal intensive care unit (NICU). Inadequate knowledge regarding the underlying pathophysiology of this disease has contributed to the minimal progress made in decreasing the incidence and severity of NEC. Because of an improved survival rate of the most immature infants, the number of diagnosed cases of NEC is anticipated to increase. Unfortunately, decades of research have failed to reduce the risk or improve the prognosis of NEC, magnifying the need for risk-reduction strategies for decreasing significant NEC-related morbidity and mortality. Advancements in our understanding of this disease process have facilitated the development of several strategies that have been investigated in the risk reduction of NEC. This article discusses the pathophysiology and causes of NEC and presents strategies investigated regarding risk reduction of this devastating disease.